Prevention of UV-carcinogenesis through DNA methylation-dependent immunomodulation

 描述(由申请人提供)：美国每年约有130万新确诊的非黑色素瘤皮肤癌病例对公共卫生和医疗保健支出产生巨大影响。因此，迫切需要安全有效的化学预防策略。过度暴露于太阳紫外线(UV)辐射是一个主要的危险因素，紫外线诱导的免疫抑制在皮肤癌的发生中起着关键作用。紫外线照射可诱导炎性介质，损害树突状细胞(DC)和效应T细胞的功能，并诱导抑制性T细胞。紫外线诱导的表观遗传修饰，如DNA超甲基化，似乎在皮肤光损伤中起着重要作用。现在出现了一种模型，认为包括DNA超甲基化在内的表观遗传修饰是由UVB诱导的炎症介质(如环氧合酶-2(COX-2)/前列腺素E2)诱导的，并在炎症介质和受损的DC功能之间起到机制上的联系。我们已经证明，局部给药和厚朴酚，一种来自厚朴植物的植物化学物质，可以防止小鼠的光癌和UVB诱导的免疫抑制。我们的初步数据进一步表明，和厚朴酚可以纠正或抑制紫外线照射下的树突状细胞中的DNA超甲基化，从而恢复树突状细胞介导的活动，包括对细胞的刺激。我们建议验证这一创新假设，即和厚朴酚抑制UVB诱导的DNA超甲基化是其对UV诱导的免疫抑制的化学预防作用的关键。我们提出了三个相互关联的特定目标来在小鼠模型中验证这一假设：(1)确定和厚朴酚是否通过紫外线暴露的皮肤中的DNA去甲基化而抑制UV诱导的免疫抑制，以及炎症介质是否在其中发挥作用；(2)确定和厚朴酚是否抑制UV诱导的耐受DC的发展，这是否通过抑制DNA超甲基化来实现；以及(3)确定和厚朴酚是否通过促进T细胞激活来抑制UV诱导的免疫抑制，以及这是否通过抑制DNA超甲基化来介导。将利用多种方法的组合来验证结果，包括使用COX-2缺陷小鼠。创新：拟议的研究将：(1)确定局部或口服给药和厚朴酚纠正紫外线诱导的免疫抑制和防止光癌发生的机制，从而为这种有希望的植物化学物质的进一步临床开发提供所需的数据；以及(2)产生的数据将为研究中波紫外线诱导DC中DNA甲基化的机制提供关键见解，并确定靶向这些机制是否足以防止中波紫外线诱导的免疫抑制。影响：使用和厚朴酚开发新的早期干预策略可能有助于降低人类患皮肤癌的风险，因为皮肤癌的风险是一个主要的公共卫生问题。

 DESCRIPTION (provided by applicant): The approximately 1.3 million new cases of nonmelanoma skin cancers diagnosed each year in the USA have a tremendous impact on public health and healthcare expenditures. Therefore, safe and effective chemopreventive strategies are urgently needed. Overexposure to solar ultraviolet (UV) radiation is a primary risk factor and that UV-induced immunosuppression plays a critical role in skin carcinogenesis. It is well established that UV irradiation induces inflammatory mediators, impairs the function of dendritic cells (DC) and effector T cells and induces suppressor T cells. UV-induced epigenetic modifications, such as DNA hypermethylation, seem to play an important role in photodamage of the skin. A model is now emerging that suggests that epigenetic modifications, including DNA hypermethylation, are induced by UVB-induced inflammatory mediators, such as cyclooxygenase-2 (COX-2)/prostaglandin E2, and act as a mechanistic link between the inflammatory mediators and compromised DC function. We have demonstrated that topical administration of honokiol, a phytochemical from the Magnolia plant, prevents both photocarcinogenesis and UVB-induced immunosuppression in mice. Our preliminary data further indicate that honokiol can correct or inhibit DNA hypermethylation in UV-exposed dendritic cells and that this restores dendritic cell-mediated activities including stimulation of cells. We propose to test the innovative hypothesis that inhibition of UVB-induced DNA hypermethylation by honokiol is critical for its chemopreventive effects on UV- induced immunosuppression. We propose three inter-related Specific Aims to test the hypothesis in a mouse model: (1) Determine whether honokiol-induced inhibition of UV-induced immunosuppression occurs through DNA demethylation in UV-exposed skin and whether the inflammatory mediators play a role in this; (2) Determine whether honokiol inhibits the development of UV-induced tolerogenic DCs and whether this is mediated through inhibition of DNA hypermethylation; and (3) Determine whether honokiol inhibition of UV- induced immunosuppression occurs through enhancement of T cell activation and whether this is mediated through inhibition of DNA hypermethylation. A combination of approaches will be utilized to verify the results including the use of COX-2 deficient mice. Innovation: The proposed studies will: (1) Identify the mechanisms by which topical or oral administration of honokiol acts to correct UV-induced immunosuppression and prevent photocarcinogenesis, thereby providing data needed for further clinical development of this promising phytochemical; and (2) The data generated will provide critical insights into the mechanisms that elicit UVB- induced DNA hypermethylation in DC and establish whether targeting of these mechanisms is sufficient to prevent UVB-induced immunosuppression. Impact: The development of new early intervention strategies using honokiol may help to reduce the risk of skin cancer in humans, as the risk of skin cancer is a major public health concern.